Associations of a Breast Cancer Polygenic Risk Score With Tumor Characteristics and Survival
Authors: Josephine M.N. Lopes Cardozo, Irene L. Andrulis, Stig E. Bojesen, Thilo Dörk, Diana M. Eccles, Peter A. Fasching, Maartje J. Hooning, Renske Keeman, Heli Nevanlinna, Emiel J.T. Rutgers, Douglas F. Easton, Per Hall, Paul D.P. Pharoah, Laura J. van 't Veer, Marjanka K. Schmidt, Thomas U. Ahearn, Hoda Anton-Culver, Volker Arndt, Paul L. Auer, Annelie Augustinsson, Laura E. Beane Freeman, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Manjeet K. Bolla, Bernardo Bonanni, Terry Boyle, Hermann Brenner, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Nicola J. Camp, Federico Canzian, Fatima Cardoso, Jose E. Castelao, Melissa H. Cessna, Tsun L. Chan, Jenny Chang-Claude, Georgia Chenevix-Trench, Ji-Yeob Choi, Sarah V. Colonna, Ellen Copson, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Caroline A. Drukker, Alison M. Dunning, Miriam Dwek, A. Heather Eliassen, Christoph Engel, D. Gareth Evans, Jonine D. Figueroa, Olivia Fletcher, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, José A. García-Sáenz, Jeanine Genkinger, Graham G. Giles, Anna González-Neira, Pascal Guénel, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Mikael Hartman, Bernadette A.M. Heemskerk-Gerritsen, Alexander Hein, Weang-Kee Ho, Reiner Hoppe, John L. Hopper, Richard S. Houlston, Anthony Howell, David J. Hunter, Hidemi Ito, Anna Jakubowska, Helena Jernström, Esther M. John, Nichola Johnson, Michael E. Jones, Vijai Joseph, Rudolf Kaaks, Daehee Kang, Sung-Won Kim, Cari M. Kitahara, Linetta B. Koppert, Veli-Matti Kosma, Peter Kraft, Vessela N. Kristensen, Katerina Kubelka-Sabit, Stella Koutros, Allison W. Kurian, Ava Kwong, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Jan Lubiński, Michael Lush, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Keitaro Matsuo, Dimitrios Mavroudis, Kyriaki Michailidou, Roger L. Milne, Nur Aishah Mohd Taib, Anna Marie Mulligan, Patrick Neven, William G. Newman, Nadia Obi, Kenneth Offit, Andrew F. Olshan, Sue K. Park, Tjoung-Won Park-Simon, Alpa V. Patel, Dijana Plaseska-Karanfilska, Coralie Poncet, Ross L. Prentice, Nadege Presneau, Renate Prevos, Katri Pylkäs, Paolo Radice, Gad Rennert, Hedy S. Rennert, Atocha Romero, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Lukas Schwentner, Christopher Scott, Mitul Shah, Chen-Yang Shen, Xiao-Ou Shu, Xueling Sim, Melissa C. Southey, Jennifer Stone, Daniel O. Stram, Rulla M. Tamimi, Soo Hwang Teo, Lauren R. Teras, Mary Beth Terry, Katarzyna Tomczyk, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Chantal van Ongeval, Qin Wang, Barbara Wappenschmidt, Camilla Wendt, Robert Winqvist, Alicja Wolk, Anna H. Wu, Siddhartha Yadav, Cheng Har Yip, Wei Zheng, Argyrios Ziogas
Journal: Journal of Clinical Oncology (2023)

PURPOSE A polygenic risk score (PRS) consisting of 313 common genetic variants (PRS 313 ) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS 313 with clinicopathologic characteristics of, and survival following, breast cancer. METHODS Women with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS 313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS 313 (continuous, per standard deviation) with overall survival (OS) and breast cancer–specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment. RESULTS The PRS 313 was associated with more favorable tumor characteristics. In BCAC, increasing PRS 313 was associated with lower grade, hormone receptor–positive status, and smaller tumor size. In MINDACT, PRS 313 was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS 313 was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent. CONCLUSION An increased PRS 313 is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS 313 has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS 313 as increasing PRS 313 is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs.